Editorial: direct-acting antivirals significantly improve quality of life in patients with HCV

Aliment Pharmacol Ther.

INVITED EDITORIALS

Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection 
Authors S. Sanagapalli, M. Danta

First published: 17 January 2018
DOI: 10.1111/apt.14467

Abstract
Linked Content
This article is linked to Younossi et al and Younossi papers. To view these articles visit https://doi.org/10.1111/apt.14423 and https://doi.org/10.1111/apt.14481.

The effect of direct-acting antiviral chronic Hepatitis C (HCV) therapies on patients’ quality of life has been a topic of minor attention compared with their impressive effects on virological endpoints. Yet, therapeutic benefits on quality of life are important to patients, and knowledge regarding such benefits may be an important tool in improving compliance in real-world scenarios.[1] For this reason, Younossi and colleagues are to be commended for their study, which describes clinically significant improvements in almost all measured physical and mental health-related quality of life outcomes following therapy with sofosbuvir and velpatasvir with or without voxilaprevir.[2] This replicates findings from other direct-acting antiviral regimens, but also confirms our own observations from clinical experience using these drugs.

Comparison with quality of life data from the interferon era may help us to tease out the mechanisms behind these findings. First, impairments in both mental and physical aspects of quality of life have long been described in chronic HCV, with or without cirrhosis, using the SF-36, one of the four instruments used in this study.[3] Second, very similar improvements in quality of life parameters were described 24 weeks after completion of interferon-based therapy, with the benefit confined only to those with sustained virological response.[4] More recent data comparing interferon-containing to interferon-free regimens clearly demonstrates that while both regimens result in equivalent improvements in quality of life (in responders) post therapy, the interferon-containing treatments are associated with significant worsening of quality of life during therapy. In contrast, quality of life seems to be improved early during interferon-free therapy and improves further following completion of successful treatment.[5, 6] Taken cumulatively we can infer that virological clearance plays a key role in improvement of quality of life, but cannot be the only factor, since improvement continues long after the virus has completely cleared from the serum.

What might such other factors be? The authors propose that improvement of liver function may play a role, though this still fails to explain the persistent improvement in benefit in non-cirrhotics post therapy. On the other hand, cerebral inflammation due to chronic HCV may explain some of the findings. Magnetic resonance spectroscopy and positron emission tomography scanning have demonstrated significant metabolic abnormalities in the brains of noncirrhotics with HCV, implying a low-grade inflammatory state, with the microglial cells being a focus of activation.[7, 8] In a small study, Byrnes and colleagues demonstrated that successful treatment with pegylated interferon and ribavirin led to normalisation of these central nervous system metabolic changes. Crucially, however, normalisation occurred gradually and improvement in metabolic abnormalities continued until 12 weeks post therapy, implying that the neuroinflammatory process may take time to settle after HCV therapy.[9] While the underlying mechanisms for improved quality of life are of interest, this study adds to the weight of evidence for the overall benefits of direct-acting antiviral therapies for HCV.

http://onlinelibrary.wiley.com/doi/10.1111/apt.14467/full

Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection—Author's reply
Z. M. Younossi

First published: 17 January 2018
DOI: 10.1111/apt.14481

Abstract
Linked Content
This article is linked to Younossi et al and Sanagapalli and Danta papers. To view these articles visit https://doi.org/10.1111/apt.14423 and https://doi.org/10.1111/apt.14467.

We appreciate the Editorial comments by Drs. Sanagapalli and Danta about our recent study reporting patient-reported outcomes in patients with hepatitis C virus infection who were treated with sofosbuvir (SOF), velpatasvir (VEL) with or without voxilaprevir (VOX).[1, 2] We agree with their comments and would like to emphasise the importance of these findings in the context of the “comprehensive benefit” of HCV cure.

To fully understand the comprehensive benefit of HCV treatment, we believe it is important to assess the comprehensive impact of HCV infection including all the pertinent clinical consequences (hepatic and extrahepatic manifestations of HCV infection), the impact on patient-reported outcomes (health-related quality of life or HRQL) and the economic burden of HCV (resource utilisation and cost of illness).[3] Similarly, the benefit of anti-HCV treatment must be assessed in this comprehensive manner.[3] The most clinically relevant endpoint of HCV treatment is achieving sustained virologic response (SVR), a surrogate of improving survival by reducing the hepatic and extrahepatic complications.[3] Another important endpoint of HCV treatment should be its positive impact on patient-reported outcomes, a surrogate of HCV patients' experience.[4] Finally, we must assess the impact of anti-HCV treatment on important economic outcomes (resource utilisation, cost of illness, cost-effectiveness of treatment) must also be assessed.[5] Although the total impact of HCV infection has been well established,[3, 6] the comprehensive benefit of “HCV cure” has only recently been recognised.[1-6] In this context, our study provides additional evidence that the new regimen of SOF/VEL+/-VOX not only has superior clinical outcomes (high SVR) but also improves patient-reported outcomes during treatment and after SVR.[2]

In their Editorial, the authors have reflected about the mechanism of patient-reported outcome improvement post-SVR-12; we agree that this improvement is partly related to viral eradication. It is plausible that the additional patient-reported benefits of SVR may be related to the amelioration of the inflammatory environment of chronic hepatitis, which takes longer to resolve. This “inflammatory milieu” of HCV infection may exert its influence on the brain or the periphery of the infected patients. In fact, HCV has been associated with a number of extrahepatic manifestations such as neuropsychiatric diseases, chronic fatigue and others.[7, 8] In this context, neurocognition, fatigue and their changes after SVR may be differentially affected which in turn can influence changes in patient-reported outcome scores.[7, 8] In fact, the impact of SVR on fatigue has been recently substantiated and the data have shown that while most patients with HCV improve fatigue scores post-SVR, some do not improve.[9] Furthermore, these subjects who continue to report disabling fatigue post-SVR seem to have significant comorbidities such as depression, anxiety, type 2 diabetes.[9] Nevertheless, in the majority of HCV subjects with SVR, fatigue continues to improve and seems to maximise by post-treatment week 48.[10]

In summary, we believe that the initial patient-reported outcome improvements are due to viral eradication. The subsequent improvement may be due to a number of post-SVR changes including improvement of the inflammatory milieu and its impact of HCV on the brain and other extrahepatic targets. In contrast, patients with HCV who continue to show residual patient-reported outcome impairments post-SVR seem to have other comorbidities, which will require other treatment modalities to optimise their well-being. In this context, we believe that patient-reported outcomes must be a routine part of assessment of any chronic liver disease. These assessments will complement the clinical outcomes and provide evidence for the comprehensive impact of treatment on the patients and the society.

http://onlinelibrary.wiley.com/doi/10.1111/apt.14481/full

Sleep disturbances in patients with hepatitis C virus infection

Found in Articles In Press 

February issue: Journal of Hepatology

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 

Daniel Shouval

Discussion (In Press Accepted Manuscript)

15 January 2

Discussion: The impact of chronic hepatitis C infection on the circadian clock and sleep

Discussion refers to article: Active at night, sleepy all day - Sleep disturbances in patients with hepatitis C virus infection 
Free abstract 

Accepted Manuscript

15 January 2014 - Daniel Shouval
Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel
PII: S0168-8278(14)00046-4
DOI: http://dx.doi.org/10.1016/j.jhep.2014.01.004
Reference: JHEPAT 4998
To appear in:Journal of Hepatology
Received Date: 8 January 2014
Accepted Date: 8 January 2014 

The impact of chronic hepatitis C infection on the circadian clock and sleep 

"In summary the discussed report provides descriptive evidence that a history of past or present mild chronic hepatitis C virus infection even without clinical evidence for cirrhosis or "traditional" hepatic encephalopathy is associated with an altered sleep pattern which has a negative impact on quality of life and well being."

No abstract is available, view the article below or PDF online.

Sleep disturbance with reversal of the day and night cycle is a well known phenomenon in patients with hepatic encephalopathy irrespective of etiology as shown in animal models and in humans 1-3
Indeed, insomnia, fatigue, depression and cognitive impairment are common symptoms in patients with chronic liver disease (CLD) with cirrhosis. During the past 15 years, several studies have been published on the impact of cirrhosis such as primary biliary cirrhosis, non-alcoholic fatty liver disease and Wilson's disease on the quality of sleep 4-6 . However, it is less known that abnormal sleep patterns have also been documented in up to~ 50% of patients with cirrhosis in the absence of overt hepatic encephalopathy or even in patients with CLD without cirrhosis 5 . It is however sometimes difficult to differentiate between an organic cause of fatigue and insomnia from psychiatric disorders of variable severity in CLD in general and in chronic hepatitis C patients in particular 7 . Sleep patterns are dictated by 24 hour circadian clocks, subjected to light and darkness cycles, which control numerous metabolic activities such as body temperature, blood pressure, melatonin, cortisol and growth hormone levels, urine output as well as mood and cognitive abilities. Such endogenous circadian cycles exist not only in humans but also in animals, plants, algae, bacteria and fungi 8 . Disruption of clock genes which control the circadian rhythms have recently been linked to sleep disorders and have an impact on metabolic activities 9,10 . Sleep and circadian rhythms disruption may have serious consequences on emotional, cognitive and somatic responses. For example, inadequate sleep may lead to exhaustion, increased irritability, mood fluctuation such as depression, anxiety or anger, reduced concentration, attention deficit dis order, decreased memory, decreased productivity and creativity, drowsiness, unintended sleep, weight gain, metabolic abnormalities such as hyperglycemia and m ore 11 . (The interested reader is referred to a recent review entitled "Sleep Disorders in Chronic Liver Disease" 3 ).

In the past two decades, referral of patients with chronic hepatitis C (CHC) is dominating the practice of clinical hepatologist worldwide, yet sleep disturbances in CHC patients without cirrhosis have received relatively little attention 3,12,13. In the present issue of the journal, Dr Heeren and co-workers from the Hannover Medical School in Germany report their observations on altered sleep quality in a cohort of CHC patients without overt cirrhosis or classical hepatic encephalopathy 14 . The study cohort (N=20, mean age 56.8y) was recruited f rom a small subgroup (N=143) 2 of the original HCV infected 1833 women who received an HCV contaminated anti-D immunoglobulin over three decades ago 15 . Thus twenty anti-HCV positive, genotype 1b patients of whom 12 were still HCV-RNA positive by PCR participated in the study. The control population consisted of 1 9 age matched healthy females (mean age 55.3y). The unique characteristic relevant to the goals of the discussed study is the relatively benign course of CHC without cirrhosis over a period of more than thirty years in this selected group of women who nevertheless complained among other symptoms of weakness, fatigue and decreased exertional capacity.

The methodology used to assess the various study variables is broad and quite complex. Participants were asked to fill a number of questionnaires including the Pittsburgh Sleep Quality Index measuring sleep quality; the Epworth Sleepiness Scale measuring daytime sleepiness; the Fatigue Impact Scale measuring the impact of fatigue on daily activity; the Back Depression Inventory measuring depression; the Hospital Anxiety and Depression Scale measuring emotional alteration and the SF-36 questionnaire measuring health related quality of life.

Furthermore, patients had to fill a sleep diary and use an actigraph which is a wrist worn device for monitoring of motor activity over a period of 24 hours/day for 5 days. Obtained scores from the various questionnairs filled by the study and contr ol groups as well as actigraphy scores were compared and a Spearman correlation tes t was used to evaluate a relationship between fatigue, quality of life, sleep parameters and actigraphy results.

The major findings of this study indicate that in contrast to healthy controls, patients with a history of chronic hepatitis C virus infection without overt cirrhosis may develop a disrupted circadian rhythm. This so called circadian arrhythmia is associated with an altered sleep pattern, insomnia , fatigue, depression and reduced quality of life which correlate with one an other. Although patients displayed an increased nocturnal activity, no correlation could be established between fatigue and sleep pattern abnormality and 24 hour activity level.

Comments: The reported results suggest and confirm previous observations that sleep disruption and its consequences should be regarded as an extra hepatic manifestation of chronic hepatitis C.

Furthermore, these symptoms may already be present in patients with mild chronic hepatitis C without clinical evidence for cirrhosis. A previous report found a strong association between reduced survival and sleep disorders in patients with advanced liver disease 16 . The present cohort of patients with relatively mild CHC is already followed for more than 3 decades and so far there is apparently no indication to suspect a worse prognosis despite the reported abnormal sleep pattern. Interestingly, the abnormal sleep pattern was present in both the 12 viremic patients as well as in those 7 patients who were HCV- RNA negative by PCR. In this context it is worthwhile to mention a recent report 3 suggesting that primary and precursor forms of live r specific microRNA (miR122) are regulated in a circadian rhythm in the liver of animals 17. In the detailed and well referenced discussion of this paper, the authors express their belief that based on previous functional imaging studies, the described symptoms in both HCV-RNA positive and negative patients are the result of an encephalopathy which is independent of the state of viremia. However, the relatively small sample size and the absence of functional imaging data for the specific study cohort does not enable yet a firm conclusion regarding the role of viremia in the above described symptoms.

Heeren and co-workers' report is the result of an extensive effort which is a case control study and descriptive by nature. The investigators utilized a wide range of methods to reach their conclusions but their results do not provide a clue regarding the mechanism(s) involved in the sleep disturbance and its consequences in CHC and this will remain a goal of future research. Aberrant sleep patterns have previously been linked to central nervous system involvement in persistent HCV infection affecting up to 65% of CHC patients 12,13,18 . It has been suggested that sleep and the circadian system regulate a number of immune functions or vice versa 19,20 . For example, the number of undifferentiated naïve T cells and production of pro- inflammatory cytokines peak during early nocturnal sleep while cytotoxic NK cells and anti-inflammatory cytokines peak during day time 19 . The impact of past or present HCV infection on these parameters in the context of sleep disturbances is still unknown. Sleep and the circadian timing systems are driven by a complex interaction between multiple brain regions, neurotransmitters and hormones. Moreover, up to 20 clock genes and their protein products have been linked to control of circadian rhythms through translational- transcriptional feedback loops 8,11. However the interaction of the hepatitis C virus with these genes and its impact on the molecular clock is still unexplored except for a recent observation in vitro that a circadian protein called PER2 interferes in viral r eplication 21 .

In summary, the discussed report provides descriptive evidence that a history of past or present mild chronic hepatitis C virus infection even without clinical evidence for cirrhosis or "traditional" hepatic encephalopathy is associated with an altered sleep pattern which has a negative impact on quality of life and well being.

References 

Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function

Postgrad Med J 2013;89:433-439 doi:10.1136/postgradmedj-2012-131185 

                                                                                             

Original article

Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function

1. Jefferson Abrantes1,
2. Daniel Simplício Torres1,
3. Carlos Eduardo Brandão de Mello2

+ Author Affiliations

1. ¹Department of Neurology, Federal University of the State of Rio de Janeiro (Universidade Federal do Estado do Rio de Janeiro), Rio de Janeiro, RJ, Brazil
2. ²Department of Gastroenterology, Federal University of the State of Rio de Janeiro (Universidade Federal do Estado do Rio de Janeiro), Rio de Janeiro, RJ, Brazil.

1. Correspondence to Dr Jefferson Abrantes, QRSW 07 Bloco A-12 Apto 303. CEP: 70675712. Sudoeste. Brasília, Distrito Federal, Brazil; jeffabrantes@uol.com.br

• Received 1 June 2012
• Revised 7 November 2012
• Accepted 3 April 2013
• Published Online First 26 April 2013

 Abstract

Purpose of the study
Hepatitis C virus (HCV) is associated with neuropsychiatric complaints. Previous studies have associated cognitive alterations with HCV infection but have often included confounding factors in their samples. This study compares the cognitive performance between patients with HCV infection (HCV patients) and a control group while excluding other factors that may cause cognitive impairment.
                                

Study design
This cross-sectional study was conducted from March 2010 through June 2011. HCV infected patients and healthy individuals between the ages of 18 and 80 years were considered eligible. The exclusion criteria included well established causes of cognitive impairment such as depression and cirrhosis. Study participants underwent neuropsychological testing involving measures of attention, memory, abstraction, visuoconstructive abilities, and executive function.
                                

Results
Of 138 initial patients, 47 were excluded because of their medical records, three refused to participate, 23 did not attend the consultation, and 32 were excluded because of having Beck Depression Inventory (BDI) scores >11. In all, 33 patients underwent neuropsychological testing; however, three were excluded because of having hypothyroidism, and one was excluded because of having a cobalamin deficiency. For the control group, of the 33 healthy individuals that were selected, four were excluded because of having BDI scores >11. Thus, the final analysis included 29 HCV patients and 29 control participants. The groups did not differ in education, age, or gender. No statistically significant differences were found between the groups regarding cognitive performance.
                                

Conclusions
In this study using strict selection criteria, there was no evidence of an association between HCV infection and cognitive impairment.

 

Introduction

Hepatitis C is caused by the hepatitis C virus (HCV), an RNA virus of the genus Hepacivirus and family Flaviviridae. Studies indicate that approximately 60–85% of people exposed to HCV develop chronic infection.1 Globally, the number of people infected with HCV is estimated to be between 130–170 million, and HCV infection is five times more prevalent than human immunodeficiency virus (HIV) infection.1 Since the 1989 publication detailing the discovery of HCV, various diseases with different physiopathological and epidemiological bases have been associated, most anecdotally, with chronic HCV infection.2 ,3 It is estimated that 40–74% of patients infected with HCV will experience at least one extrahepatic manifestation within their lifetime.4

Cognitive changes have been well documented in patients with chronic hepatopathy, most often as a result of hepatic encephalopathy related to uncompensated liver cirrhosis.5 However, a growing body of evidence has demonstrated that cognitive changes may also occur before the development of liver cirrhosis.6 Neuropsychiatric symptoms such as ‘brain fog’, fatigue, and weakness occur in approximately 50% of patients with HCV, independently of the severity of the hepatic involvement. These complaints do not seem to be related to HCV genotype or replication.7

Forton et al reported the first evidence of brain metabolic changes in patients with HCV, distinct from the alterations found in hepatic encephalopathy.8 The occurrence of cognitive deficits in this group of patients may be due to the direct action of the virus in the central nervous system (CNS) or indirectly through production of cytokines.7

Several studies have suggested that a relationship may exist between HCV and cognitive dysfunction. However, these studies frequently included patients with well established causes of cognitive impairment, such as the use of illicit drugs, interferon, depression, and cirrhosis.7

Given the lack of controls for these potential confounding variables in previous studies, broad and rigorous exclusion criteria were employed in this study to avoid the inclusion of individuals with known risk factors for cognitive impairment. The objective of the current study was to compare the cognitive performance in HCV patients and a control group of healthy individuals, while excluding any participants with conditions that might interfere with cognitive performance.

Methods

Study design

The current study was an observational, cross-sectional study with paired controls.

Inclusion criteria

This study was conducted at the Gaffrée e Guinle University Hospital (HUGG) of Rio de Janeiro, Brazil, from March 2010 through June 2011. The hospital's gastroenterology service reviews about 4800 patients with hepatitis C annually. All HCV infected patients (with detectable serum HCV RNA) who were being tracked in the hepatology outpatient clinic between the ages of 18 and 80 years were considered eligible. The control group was composed of individuals accompanying the outpatients and inpatients at the HUGG who were between 18 and 80 years old.

Exclusion criteria

Many factors can provoke cognitive changes.9 Therefore, in an effort to avoid confounding factors, the following exclusion criteria were established: education of less than 4 years; history of encephalic vascular accident, encephalic cranial trauma, dementia, Parkinson's disease, multiple sclerosis, neurodegenerative disease, chronic obstructive pulmonary disease, congestive cardiac insufficiency, other viral infections (HIV, hepatitis B virus (HBV), human T lymphotropic virus (HTLV)), syphilis, significantly compromised liver function, depression, psychiatric illness, illicit drug use, psychotropic drug use, alcoholism, hypothyroidism, cobalamin or folic acid deficiency; and previous or current use of interferon.

Neuropsychological assessment

The cognitive evaluation was performed in a soundproof room under adequate lighting conditions. Two neurologists trained in the administration of neuropsychological tests, who had knowledge of the blood status of the individuals, conducted the cognitive assessment. Study participants were asked about the use of illicit drugs, alcoholic beverages and psychoactive substances 48 h before neuropsychological testing.

The patients underwent neuropsychological testing by answering questions regarding predefined cognitive complaints (poor memory, dispersal/distractibility, difficulty in performing two tasks simultaneously, and difficulty driving) and were given additional space for spontaneous complaints. The following tests were used.

Mini-Mental State Exam

This test is widely used as a brief screening instrument for cognitive impairment. The cognitive functions assessed in this test are attention, calculation, language, praxis, orientation, memory, and attention span.10 The Mini-Mental State Exam was applied according to the adaptations and recommendations of the Brazilian Academy of Neurology.11

Simple Drawing Test

This test assesses visual identification and incidental, immediate, and delayed visual memory. The test sheet comprises 10 drawings. The score indicates the number of correct responses at each step of the test.12

Rey Auditory Verbal Learning Test

This test assesses immediate and delayed verbal memory and evaluates the patient's ability to learn. The Portuguese translated and adapted version of the Rey Auditory Verbal Learning Test (RAVLT) was used.13 RAVLT scores include the sum of the number of words remembered after five repetitions of a list A (A1–A5) and measures of retroactive interference (A6/A5), proactive interference (B1/A1), forgetfulness (A7/A6), and recognition

Reverse Numerical Order Test

This test is a component of the Wechsler Intelligence Scale for Adults-III (WAIS-III), which is used to investigate working memory. The score indicates the number of numerical sequences that the patient correctly repeats in reverse order.10

Direct Numerical Order Test

The number of digits repeated (in forward order) on the WAIS-III provides an easily administered objective measure of the ability to maintain auditory attention for a brief period.14

Trail-Making Test

The Trail-Making Test (parts A and B) represents one of the most widely used tests for assessing divided attention. The score is based on the time taken to execute specific tasks. If this time exceeds 5 min, the test is discontinued.10 The ratio between the execution times of part B and part A provides an assessment of non-verbal executive function.15

‘A’ Random Letters Test

This test assesses sustained attention and consists of a series of random letters among which a target letter appears with greater-than-random frequency. The score is the sum of the number of errors.14

Stroop Test

The Stroop Test, as modified by Dodrill, is considered one of the best tests of selective attention.10 This test evaluates the performance of the individual (ie, time required to complete each of the two parts of the test) and the difference between these times. The test is stopped if the time required to complete either task exceeds 5 min.10 ,16

Boston Naming Test

This test was used in the Brazilian version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD). In this test, 15 designs are presented to the individual. One point is given for each correct answer, yielding a maximum score of 15 points.10 ,17

Verbal Fluency Test

The Verbal Fluency Test of a semantic category (animals) was used to assess verbal executive function. The score is the number of items spoken (excluding repetitions) in 1 min.12

Clock Drawing Test

In addition to evaluating non-verbal executive function, this test covers many other cognitive domains, including verbal comprehension, attention, and constructive abilities. The method chosen was that described by Shulman.18

Copies of Geometric Shapes (CERAD)

This test is used to assess visuoconstructive skills.17 The criteria chosen for correction and punctuation have been published by Rosen et al.19

Symbol Search Test

The Symbol Search Test is a component of the WAIS-III that is used to investigate processing and learning speed. The test is stopped upon reaching 120 s.20

Similarities Test

The Similarities Test of the WAIS-III is used to evaluate conceptualisation and abstraction. The individual is asked to identify the characteristic that is shared by two objects or concepts. The test is discontinued after four consecutive errors.20

Depression screening

The Portuguese language adapted version of the Beck Depression Inventory (BDI) was used to screen for depression. The BDI has been used in many clinical trials involving patients with HCV.21–23

Holtzheimer et al23 reported that the BDI has a diagnostic sensitivity of 91% for depression using the traditional cut-off point >10 in a population of drug users with HCV. Analysis of the receiver operating characteristic (ROC) curve showed that a cut-off of 11 has a sensitivity of 91% and a negative predictive value of 92%. Low specificity (63%) and low positive predictive (59%) value are among the limitations of using the BDI.

In the Brazilian version of the BDI, scores between 0 and 11 are indicative of the absence of depression.21 Therefore, to avoid the inclusion of patients with depression in the study (which could result in a type I error), a BDI cut-off point of 11 was used.

Assessment of hepatic involvement

Biopsies performed in the 12 months before the study were considered valid for the evaluation of the degree of hepatic impairment. The aspartate aminotransferase/platelet ratio (APRI) was calculated for all patients. An APRI ≥1.5 indicates the presence of significant fibrosis, whereas levels ≤0.5 indicate the absence of significant fibrosis. Using a cut-off of ≤1.0 allowed us to exclude the presence of cirrhosis with a sensitivity of 89% and a specificity of 75%.24 The presence of advanced fibrosis or cirrhosis in a liver biopsy sample (F3 or F4 in the METAVIR classification system, respectively) or an APRI >1 defined a significantly compromised liver. 

Blood tests

Blood tests were performed on all patients after the cognitive analysis. Serum sodium, thyroid stimulating hormone (TSH), free thyroxine (T4), cobalamin, folic acid, VDRL (Venereal Disease Research Laboratory, syphilis), HIV, HBV, and HTLVI/II tests were analysed.

 

Data analysis

The Kolmorov–Smirnov test was used to analyse the hypothesis of normality of the sample. Inter-group comparisons were made with the Student t test or the Mann–Whitney test according to the distribution of variables.

Inter-group differences in reporting cognitive complaints and difference in gender were assessed by Fisher’s exact test.

All tests were two-tailed and statistical significance was set at p<0.05. Data were recorded and analysed using SPSS V.15 for Windows.

                                

Ethical aspects

The research ethics committee of the HUGG approved the study, which adhered to the guidelines of the Helsinki declaration. Study participants completed a free and informed consent form after receiving a detailed explanation of the study.

                          

Results

Study sample

A total of 138 patients met the initial eligibility criteria, and 47 patients were excluded because their medical records contained one or more of the previously determined exclusion criteria (figure 1).

Figure 1                                       

Patients excluded after medical analysis. HBV, hepatitis B virus; HIV, human immunodeficiency virus; HTLV, human T lymphotropic virus. Access the article online to view this figure in colour.

Consultations to apply the BDI were scheduled for the 91 remaining patients. Of these, 23 patients did not attend the consultation, three patients withdrew from participation in the study, and 32 patients received a score >11 on the BDI. The 33 remaining patients underwent neuropsychological testing and blood sample collection. Three patients were excluded because of hypothyroidism, and one patient was excluded because of vitamin B12 deficiency (figure 2).

                                

Figure 2

Flow diagram of the selection of patients in the hepatitis C virus group. BDI, Beck Depression Inventory. Access the article online to view this figure in colour.

Thirty-four healthy individuals were chosen for the control group, of whom five were excluded due to BDI scores >11. The control group was assessed following the same criteria of exclusion for the HCV group; however, these individuals were not subjected to serological tests.

Demographic data

There were no statistically significant differences in sex, age, or education level between the HCV and control groups (table 1). There were no statistically significant differences in the reporting of cognitive complaints between the HCV and control groups. Interestingly, 5/29 (17.2%) patients in the HCV group spontaneously reported complaints of fatigue, while none in the control group reported fatigue (table 2).

 

Table 1

 

Descriptive statistics for age, education level, and gender

	Group
	Control (n=29)	HCV (n=29)	p Value
Age (years)
Mean (±SD)	52.45 (±12.97)	54.10 (±12.23)	Student t test 0.62
Educational level (years)
Mean (±SD)	9.8 (±4.0)	9.7 (±3.3)	Mann–Whitney test 0.83
Gender	n (%)	n (%)
Male	14 (48.3%)	11 (37.9%)	Fisher's exact test 0.596
Female	15 (51.7%)	18 (62.1%)

Table 2

Cognitive complaints of patients in the HCV and control groups

 

	Group
	Control (n=29)		HCV (n=29)		p Value
Complaints	n	%	n	%	Fisher's exact test
Poor memory	13	44.8	13	44.8	1.000
Dispersal/distractibility	9	31.0	7	24.1	0.769
Difficulties in performing 2 tasks	2	6.9	3	10.3	1.000

• No participants in either group complained of having difficulty driving.
• Regarding other complaints, 5 individuals (17.2%) in the HCV group reported experiencing fatigue.
• HCV, hepatitis C virus.

Genotype 1 was responsible for 22/29 (78.6%) of the infections in the HCV group. A total of 17/29 (58.6%) individuals in the HCV group had liver biopsies performed in the last 12 months. Of these, 5/17 (29%) were classified as F0, 10/17 (58%) as F1, and 2/17 (11%) as F2, based on METAVIR scores. The mean and median APRIs in the HCV group were 0.41 and 0.38, respectively. The source of HCV infection was blood transfusion in 18/29 (62%), an unknown source in 10/29 (34%), and a biological material accident in 1/29 (4%) of the patients with HCV.

The 23 patients who did not attend the neuropsychological testing exhibited the following characteristics: (1) a mean of 9.2 (±3.2) years of schooling; (2) a mean age of 54.3 (±12.1) years; (3) 12/23 (52.1%) were male and 11/23 (47.9%) were female.

Neuropsychological comparison of the HCV and control groups

Statistical analyses revealed no significant differences between the groups in any of the neuropsychological tests applied (table 3).

Table 3 View this table

Neuropsychological test results for the HCV and control groups

 

Discussion

CNS involvement is observed in many viral infections, and HIV infection is currently one of the most studied. Moreover, the HCV family (Flaviviridae) includes several viruses with known neurotropic effects, such as the West Nile virus, Saint Louis encephalitis virus, Murray Valley virus, and Japanese encephalitis virus.25 Several hypotheses have been proposed to explain the occurrence of cognitive impairment in HCV infections:
                                

1. The direct action of the virus in the CNS, through a ‘Trojan horse’ effect: The infection of the CNS begins with HCV virus replication in peripheral blood mononuclear cells in the bone marrow, which subsequently serves as precursors of macrophages and microglial cells of the CNS.7 The production of tumour necrosis factor α (TNFα) and interleukin 8 (IL8) in macrophages/microglia infected with HCV may be responsible for cognitive impairment. However, data about the association between the virus in the brain and impaired cognitive function are still lacking.7
2. The direct action of the virus in the CNS through viral replication in neurons: Several factors suggest that this is not the case; for example, viral replication is very low within the brain, and HCV RNA is almost undetectable in the cerebrospinal fluid. Moreover, there is no correlation between viral load and cognitive impairment in patients with HCV infection.7
3. A side effect of the inflammatory process: The cytolytic effects of HCV within the liver activate the immune system. The chronic activation of the inflammatory system results in the production of cytokines, such as IL6, IL4, and TNFα, which are then responsible for the neuronal changes that can result in cognitive impairment.7

This study, which was developed with strict selection criteria, indicated no differences in performance on cognitive tests between patients with HCV and the control group. The groups were similar in gender, age, and education, which are known to influence cognitive testing.

The control group presented higher rates of memory problems (45%) as shown in table 2, which can raise questions about the health state of this group. However, when comparing the means obtained from both groups with the cut-off values suggested on national studies, it was observed that the performance of this group is within the normal range (table 4).11–13

Table 4

Mean obtained in cognitive testing in the study participants and cut-offs in national studies

 

Cognitive tests	Control group Mean	HCV group Mean	Cut-off in national studies
MMSE	28	27.4	25
Direct order	7.96	7.93	>4
Reverse order	4.31	4.58	>2
Verbal Fluence Test	19.13	18.55	>12
Simple Drawing Test
Incidental memory	5.86	6.34	>4
Immediate memory	8.65	8.75	>6
Later memory	8.89	9.10	>4
Rey Auditory Verbal Learning Test
Sum of A1-A5	41.86	41.34	>29.6
Retroactive interference (A6/A5)	0.83	0.79	>0.61
Proactive interference (B1/A1)	0.95	1.04	>0.48
Forgetting (A7/A6)	0.98	1.01	>0.73
Recognition	11.58	11.27	>9.42
Trail-Making Test part A	46.34	53.65	<120

• HCV, hepatitis C virus; MMSE, Mini-Mental State Exam.

Other cognitive tests used in this study were not applied previously in Brazilian studies and therefore not included.

HCV patients with advanced stages of fibrosis or cirrhosis were excluded because these patients have a high frequency of cognitive impairment. In addition to the hepatic encephalopathy that may occur in patients with significant liver impairment, some patients may have minimal hepatic encephalopathy that is detectable only through neuropsychological testing. The prevalence of minimal hepatic encephalopathy in cirrhotic patients is estimated to be between 30–80%. These patients exhibit cognitive changes that involve executive function, attention span, working memory, and visuoconstructive abilities—symptoms that are frequently reported in patients infected with

HCV.26

Because of the high prevalence of depression in patients suffering from HCV, a major concern was avoiding the inclusion of depressed participants in this study. Although there is a debate about cognitive impairment in patients with depression, two recent meta-analyses support the presence of cognitive impairment in patients with major depression. These studies demonstrate that executive function and the prefrontral cortex are affected by depression, which may impact cognitive performance.27 ,28

A recent study demonstrated the presence of cognitive changes involving working memory and verbal fluency in patients minor depression.29 Various studies have reported cognitive changes in HCV infected patients that include deficits in attention, psychomotor speed, working memory, and executive function; this pattern of frontal–subcortical cognitive dysfunction is similar to that found in patients infected with HIV. However, the inclusion of depressed patients in these studies may invalidate the assumption of an association between HCV and cognitive deficit.

Conversely, the high rates of depression reported in patients with HCV may be a neuropsychiatric manifestation resulting from the direct or indirect action of the virus in the CNS. Therefore, the exclusion of these patients may have resulted in selection bias toward patients with fewer cognitive manifestations of HCV infection.

                             

Other factors that may affect cognitive performance in some studies of HCV patients is the inclusion of patients with a history of alcohol and/or illegal drug abuse, and the inclusion of patients using psychotropic drugs or interferon. Lack of rigorous selection criteria in previous studies may have resulted in an overestimation of the prevalence of cognitive impairment associated with HCV.

                             

This study has the following limitations: (1) it was not a longitudinal study, which limits the authors’ hypothesis that the association may not exist; (2) the number of study participants was small, thus limiting the statistical power of the study; (3) the control group was composed of persons accompanying the patients—these individuals may experience anxiety disorder due to the health conditions of those patients, resulting in a negative impact on cognitive performance; (4) the control group did not undergo blood testing—thus, one cannot exclude the presence of comorbidities such as subclinical hypothyroidism that can alter the performance in cognitive assessment; (6) the examiners were not blinded to the serological status of the participants, which may influence the outcome of testing; (7) self-reporting is not the most reliable way of ensuring participants did not use illicit drugs or alcoholic beverages—the inclusion of these individuals may have had an impact on the neuropsychological tests; (8) the use of the BDI as a screening tool for depression may have resulted in the exclusion of individuals without depression, due to its low specificity.

                             
In this study there was no apparent relationship between HCV in patients without liver dysfunction, and cognitive impairment. Further studies with greater numbers of participants followed up prospectively over at least 12 months, with careful consideration for potential confounders including depression in the outcome variable analysis, are required to answer the question of a causal association between HCV and cognitive impairment in patients without liver dysfunction.
                                

Main message
In this study there is no evidence of cognitive dysfunction in hepatitis C virus carriers without comorbidities.

Current research questions
Prospective studies with large numbers of participants, with careful consideration for potential confounders, are necessary to establish the relationship between HCV infection and cognitive impairment.

Acknowledgments

We thank Carl B Dodrill, Emeritus Professor in the Department of Neurology at the University of Washington Medical School, for his kind permission to translate the Stroop test into Portuguese.

 

Footnotes

• Contributors JA performed neuropsychological testing, developed the study design and wrote the article. DST collaborated on neuropsychological testing. CEBdeM guided in preparing the study design.
• Funding The Gaffrée e Guinle University Hospital, part of the Federal University of the State of Rio de Janeiro, Brazil, paid for the laboratory tests. This is a publically financed hospital.
• Competing interests None.
• Patient consent Obtained.
• Ethics approval The research ethics committee of the Gaffrée e Guinle University Hospital approved the study according to the guidelines of the Helsinki Declaration. Study participants completed a free and informed consent form after receiving a detailed explanation of the study.
• Provenance and peer review Not commissioned; externally peer reviewed.

 

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

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